Alterations in N-methyl-D-aspartate receptor sensitivity and magnesium blockade occur early in development in the R6/2 mouse model of Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that affects primarily the striatum and cerebral cortex. A search for the factors that increase the vulnerability of striatal neurons will lead to a better understanding of the pathological cascades of this disease. A current hypothesis for neurodegeneration of striatal medium-sized spiny neurons in HD is an alteration in N-methyl-D-aspartate (NMDA) receptor function. In the present study we examined electrophysiological properties of NMDA receptors in the R6/2 transgenic mouse model. These animals express exon 1 of the human HD gene and present an overt behavioral phenotype at about 5 weeks of age. Whole-cell voltage clamp recordings from acutely dissociated striatal neurons were obtained from three different age groups of transgenic mice (15, 21, and 40 days old) and their littermate controls (WT). In transgenic animals, two groups of neurons were found with respect to NMDA and Mg2+ sensitivity. One group of R6/2 cells displayed responses similar to those of WT, whereas the other showed increased responses to NMDA and decreased Mg2+ sensitivity. These cells were encountered in all age groups. The abnormal sensitivity to NMDA and Mg2+ indicates that NMDA receptor alterations occur very early in development and suggest the presence of constitutively abnormal NMDA receptors. These alterations may contribute to an enhancement of NMDA responses at hyperpolarized membrane potentials that may be a key factor in striatal neuronal dysfunction.

Dopaminergic and Glutamatergic Signaling Crosstalk in Huntington's Disease Neurodegeneration: The Role of p25/Cyclin-Dependent Kinase 5

“…5) might sensitize mutant huntingtin striatal cells to NMDAR and D 1 R activation. Therefore, once NMDAR and D 1 R were activated, both receptors might act coordinately to promote calcium homeostasis deregulation (Cepeda et al, 2001;Starling et al, 2005;Tang et al, 2007) with the consequent mitochondrial depolarization and caspase activation (Zeron et al, 2002(Zeron et al, , 2004. In addition, as our data demonstrate, the activation of NMDAR may further potentiate D 1 R-mediated phosphorylation of Cdk5, leading to the generation of p-Cdk5/p25 complexes and enhanced Cdk5 activity.…”

“…Hypothetical model to depict the link between neurotoxicity induced by dopamine and glutamate receptor activation and the Cdk5 pathway in HD. Enhanced activation of NMDAR and D 1 R induced by mutant huntingtin leads to deregulation of calcium homeostasis (Cepeda et al, 2001;Seong et al, 2005;Starling et al, 2005;Tang et al, 2007). Increased intracellular calcium in turn leads to higher calpain activity that results in enhanced cleavage of p35 into p25 (Lee et al, 2000).…”

Allosteric activation of M 4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

“…Due to its pivotal importance in these domains, changes in striatal physiology can contribute to multiple neurological diseases, including Huntington's disease, Parkinson's disease, dystonia, and others. An increasing number of reports suggest that changes in striatal synaptic physiology, including changes at glutamatergic, dopaminergic, and cholinergic synapses, are evident beginning in the prediagnostic phase of HD (5,6,(8)(9)(10)(11)(12)(13)(14)(35)(36)(37). These changes may contribute to early motor, cognitive, and psychiatric abnormalities, and could set the stage for the extensive pathophysiological alterations appearing later in the striatum.…”

Interaction of Postsynaptic Density Protein-95 with NMDA Receptors Influences Excitotoxicity in the Yeast Artificial Chromosome Mouse Model of Huntington's Disease

“…These neurons are enriched in NR2B-containing NMDARs compared with other NR2 subunits and other brain regions (Landwehrmeyer et al, 1995;Christie et al, 2000;Li et al, 2003). Previous work in mouse and cellular models of HD suggests NR2B-containing NMDARs are functionally altered in HD and contribute to neuronal dysfunction and susceptibility to apoptosis (Chen et al, 1999;Levine et al, 1999;Cepeda et al, 2001;Zeron et al, 2001Zeron et al, , 2002Song et al, 2003;Starling et al, 2005;Tang et al, 2005;Milnerwood et al, 2006;Shehadeh et al, 2006;. However, the molecular mechanisms underlying mutant huntingtin's effect on NMDAR function have not been fully elucidated.…”